Regenerative Rehabilitative Principles in Modulating Weight Bearing and Joint Kinematics to Delay Post-Traumatic Knee Osteoarthritis

项目S U MMARY 膝盖受伤，例如，半月板撕裂，增加发生创伤后骨关节炎（PTOA）的风险 至少10倍。在美国，PTOA导致残疾，每年的医疗费用高达30亿美元。 虽然受伤后需要康复，但目前的协议仅涉及恢复受伤前的活动。 关于如何优化早期康复工作以保持长期健康， 膝盖软骨健康。使用一个完善的大鼠PTOA模型，我们建议表征膝关节的反应， 软骨的操作通常在损伤后康复期间实施的三个要素：1） 初始非负重持续时间，2）身体活动水平的改变，3）下肢偏离 关节运动学临床前大鼠模型的使用提供了对疾病时间轴的实验控制， 有助于理解PTOA的机理研究。我们的总体假设是， 强调保持受伤前膝关节负荷分布（例如，最小化负重限制， 恢复身体活动水平或减少关节运动学的偏差）将延迟PTOA。我们将 使用创新的实验方法和技术系统地测试这一假设，以解决 PTOA康复文献中的知识差距，如以下目标所述。(Aim 1）无重量 在左后肢上进行内侧半月板横断（MMT）手术后大鼠的承重持续时间 将使用后肢悬吊来改变。软骨健康的比较不同暴露的 暂停决定了初始非负重对PTOA进展的因果影响。使用后- 肢体悬吊代替肢体固定减少了关节挛缩的有害后果， 这与目前规定膝关节损伤后初始不负重的实践一致。(Aim 2）受伤后 身体活动水平将通过改变每天跑步机跑步的量来改变。大鼠伤前 将首先建立活动水平，以允许标准化量化损伤后活动改变（% 前MMT）。然后可以确定损伤后活动水平对PTOA进展的因果影响。（目标 3)将在多个时间点使用双平面X射线运动分析评估3D后肢关节运动学 在MMT之前和之后，以确定早期损伤后关节运动学偏差是否可预测 PTOA的最终严重程度。使用X射线视频直接量化3D骨骼运动可以克服 与使用皮肤标记相关的重大错误。对于所有三个目标，我们将结合我们的对比 增强的microCT分析与传统的组织病理学，以提供3D的补充评估 膝关节软骨的微观结构/组成。这项创新性工作的结果将提供深入了解 肢体负重和关节运动学损伤后康复调整的潜在因果影响， PTOA进展。这些新的知识对于推进我们对发病机制的理解至关重要 并开展转化研究，通过优化伤后康复来减少PTOA。

PROJECT S U MMARY Knee injuries, e.g., meniscus tears, increase the risk of developing post-traumatic osteoarthritis (PTOA) by at least 10 fold. PTOA leads to disability with a substantial healthcare cost of $3 billion per year in the US. Although rehabilitation is required after injury, current protocols only address the return to pre-injury activities. Critical knowledge gaps exist regarding how to optimize early rehabilitation efforts to preserve long-term knee cartilage health. Using a well-established rat PTOA model, we propose to characterize responses of knee cartilage to the manipulation of three elements commonly implemented during post-injury rehabilitation: 1) durations of initial non-weight bearing, 2) modifications of physical activity level, and 3) deviations in lower-limb joint kinematics. The use of a pre-clinical rat model provides the experimental control over disease timeline to facilitate a mechanistic study to understand PTOA. Our overall hypothesis is that post-injury interventions that emphasize maintaining pre-injury knee loading profile (e.g. minimizing weight-bearing restriction, regaining physical activity level, or reducing deviations in joint kinematics) will delay PTOA. We will systematically test this hypothesis using innovative experimental approaches and technologies to address the knowledge gaps in the PTOA rehabilitation literature as described in the following Aims. (Aim 1) Non-weight bearing durations in rats after the medial meniscal transection (MMT) surgery performed on the left hind limb will be varied using hind-limb suspension. The comparisons of cartilage health among varying exposures of suspension determines the causal effect of initial non-weight bearing on PTOA progression. The use of hind- limb suspension instead of limb immobilization reduces harmful consequences of joint contracture and is more in line with current practice of prescribing initial non-weight bearing after knee injuries. (Aim 2) Post-injury physical activity levels will be modified by varying the amount of daily treadmill running. Rats’ pre-injury activity levels will first be established to allow standardized quantification of post-injury activity modification (% of pre-MMT). The causal effect of post-injury activity level on PTOA progression can then be determined. (Aim 3) 3D hind-limb joint kinematics will be assessed using biplanar X-ray motion analysis at multiple time points before and after MMT to determine whether early post-injury joint kinematic deviations are predictive of the ultimate severity of PTOA. Using X-ray videos to directly quantify 3D bone movements can overcome the significant errors associated with the use of skin markers. For all three Aims, we will incorporate our contrast enhanced microCT analysis with conventional histopathology to provide complementary evaluations of the 3D microstructure/compositions of knee cartilage. Findings from this innovative work will provide insight into the potential causal effects of post-injury rehabilitative modifications in limb weight bearing and joint kinematics on PTOA progression. Such new knowledge is fundamental to advancing our understanding of the pathogenesis of PTOA and developing translational research to reduce PTOA by optimizing post-injury rehabilitation.